1. Technical Field of the Inventive Subject Matter
The inventive subject matter relates to novel glutamate receptors and utilization thereof; more specifically to a glutamate receptor, DNA which encodes the receptor, a transformed cell expressing the receptor, a method for producing the receptor, a method for identifying an agonist, antagonist, or allosteric modulator for glutamic acid, a method for identifying an agonist for glutamic acid, an antibody to the receptor, and processes for making glutamate receptor modulators and pharmaceutical compositions comprising said modulator.
2. Background
Glutamic acid is a major excitatory neurotransmitter in the central nervous system, and it is widely accepted that its abnormal control is involved in progressive encephalopathies such as memory disorders, ischemic encephalopathy, amyotropic lateral sclerosis (ALS), Parkinson's disease, and Huntingon's chorea (Meldrum, B. S., Neurology, 1994 November;44 (11 Supple 8):S14-23; Nishizawa, Y., Life Sci. 2001, Jun. 15;69(4):369-81). Therefore, many studies concerning glutamate receptors have been carried out up to now in cranial nerve system. Many receptors (three kinds of ionotropic receptors and eight kinds of metabotropic receptors) have been found in the central nervous system with their splicing variants as well. Particularly, since 1992 when metabotropic glutamate receptor type I (mGluR1a) was cloned by Nakanishi, et al., at least three splicing variants (mGluR1b, mGluR1c and mGluR1d) have been confirmed as mGluR1 variants (As to details, refer to Hermans, E. and Challiss, R. A., Biochemical J., 359:465-484, 2001). In all of those variants, the C-terminal region of mGluRla becomes short, and their existence in nerve cells and glia cells has been confirmed. On the basis of such abundant receptor information, development for working drugs which are specific to each receptor has been extensively carried out. Even today new therapeutic drugs in the treatment of the above-described diseases are being developed (As to details, refer to Barnard, E. A., Trends Pharmacol. Sci., 1997, May;18(5):141-8; Schoepp, D. D., Conn. P. J., Trends Pharmacol. Sci., 1993, January; 14(1):13-10).
Nowadays, we have several pieces of knowledge that suggest physiological functions of the peripheral glutamate receptor (Berk, M., Plein, H., Ferreira, D., Clin. Neuropharmacol., 2001, May-June;24(129-32; Karim, F., J. Neurosci. 2001, Jun. 1;21(11):3771-9; Berk, M., Plein, H., Belsham, B., Life Sci. 2000;66(25):2427-32; Carlton, S. M., Goggeshall, R. E., Brain Res. 1999, Feb. 27; 820(1-2):63-70; Haxhij. M. A., Erokwu, B., Dreshaj, I. A., J. Auton. Nerv. Syst. 1997, Dec. 11; 67(3):192-9; Inagaki, N., FASEB J. 1995, May; 9(8):686-91; Erdo, S. L., Trends Pharamcol. Sci., 1991, November; 12(11):426-9; Aas, P., Tanso, R., Formum, F., Eur. J. Pharamacol. 1989, May 2; 164(1):93-102; Said, S. I., Dey, R. D., Dickman, K., Trends Pharmacol. Sci. 2001, July; 22(7):344-5; Skerry, T. M., Genever, P. G., Trends Pharamacol., Sci. 2001, April; 22(4):174-81). However, those peripheral glutamate receptors are expressed in peripheral nerves, smooth muscle and immune tissues. There has been no report for their expression in epithelium of tongue and digestive tract. In mammals including humans to maintain normal growth and health, it is necessary to orally take up required amounts of nutrients at a specific timing and excrete disposable matter. This is actually done by the digestive tract, which is a single tube consisting of oral cavity, stomach, small intestine and large intestine. The process of digestion and absorption is controlled by intrinsic intestinal neuroplexus and extrinsic cranial nerves.
The judgment as to whether or not to take a necessary nutrient is the result of brain integration of a signaling pathway that the individual is aware of taste with an autonomous signaling pathway that the individual is unaware of visceral sense. It is considered that salty taste (sodium, potassium, etc.) serves as a marker of minerals and is required for maintaining the osmotic pressure of the body fluid; sweetness (glucose) serves as a marker of carbohydrates and is required for supplementing energy; umami (sodium glutamate) serves as protein marker and is useful for supplementing energy and essential amino acids; and bitterness serves as a marker for toxic substances. That is, necessary nutrients are taken up relying on the tastes thereof. Then, if necessary amounts are ingested, satiation is determined by a series of intracerebral processes coming from the signal input to the solitary tract nucleus. Those signals are derived from activated vagus afferent fibers through nutrient sensors existing in the stomach, small intestine, and hepatoportal vein (Bray, G. A., Proc. Nutr. Soc., 2000; 59:373-84; Bray G. A., Med. Clin. North. Am. 1989:73:29).
On the other hand, physiological studies on the mechanism for chemical sensation in the digestive tract have been performed for a long time. It is supposed that there are sensors that detect the content of the digestive tract (for the details, reference is made to Mei, N., J. Auton. Nerv. Syst., 1983; 9:199-206; Mei, N., Lucchini, S., J. Auton, Nerv. Syst., 1992; 41:15-8). The digestive chemosensory system includes a glucose sensor (Mei, N., J. Physiol. (Lond.) 1978, 282, 485-5-6), a temperature sensor (El Ouazzani, T., Mei, N., Exp. Brain Res. 1979; 15; 34:419-34), an osmotic pressure sensor (Mei, N., Garnier, L., J. Auton. Nerv. Syst., 1986; 16:159-70), a pH sensor, an amino acid sensor (Mei, N., Physiol. Rev., 1985; 65:211-37), and a stretch sensor (Barber, W. D., Burks, T. F., Gastroenterol Clin. North. Am. 1987; 16:521-4).
In particular, a sensor that recognizes glutamic acid was suggested by Niijima et al. from neural excitation that occurred when glutamic acid was administered in the digestive tract. In this experiment, the technique of recording neural discharge activity was used for the stomach branch and abdominal cavity branch of the vagus nerve. Those vagal branches control mainly the stomach and small intestine and responded to glutamic acid; therefore was assumed that there is a mechanism that recognizes this amino acidat the vagus nerve ending (Niijima, A., Physiol. Behav., 1991; 49:1025-8). However, no cloning has been made for such a supposed sensor that recognizes glutamic acid until Applicants' present work.